The FDA has approved tamoxifen as the first breast cancer chemopreventive agent. SERM and aromatase inhibitor therapy is effective for estrogen receptor-positive (ER+) cancers, but they are not without limitations and risks. New less-toxic chemopreventive agents are needed for the prevention of ER+ and ER- cancers (for which no suitable preventive agent is available). 9-cis-Retinoic acid (9cRA) and rexinoids like Targretin that selectively interact with nuclear retinoid X receptors (RXRs) are effective in the prevention of ER+ cancer either alone or in combination with anti-estrogens. Additionally, Targretin prevents ER- mammary cancers in transgenic mouse models. At UAB, we designed and synthesized two new classes of RXR- selective retinoids, named UAB rexinoids. We identified several different low-toxicity UAB rexinoids that are very effective in vivo in mammary cancer chemoprevention. The least toxic UAB rexinoid, 9cUAB30, does not display common lipid toxicities that have plagued the clinical use of other retinoids, like 9cRA or Targretin, for cancer prevention. 9cUAB30 has finished preclinical development by the NCI RAPIDProgram as a new chemopreventive agent. The NCI RAPID Program will fund a phase I trial on 9cUAB30 to determine human toxicity and pharmacokinetics. [In Specific Aim 1, we will design second-generation rexinoids based on x-ray crystallographic 3D structures of our active leads from two new classes of rexinoids bound to RXR. Candidate rexinoids will be crystallized with RXR and evaluated in vitro. Potent and selective RXR agonists will then advance to in vivo testing (Specific Aim 2) using our new seven-day screen for inhibition of tumor proliferation, and effects on triglyceride levels. Active rexinoids will be studied in two mammary cancer prevention models (MNU-initiated ER+ model and DMBA MMTV-erbB2 ER- transgenic model). In Specific Aim 3, our first rexinoid candidate (9cUAB30) will enter a phase Ib trial as part of our SPORE project (this will follow the NCI sponsored phase la trial in normal volunteers). In the phase Ib trial, we will evaluate whether 9cUAB30 alters proliferation, apoptosis or RXR downstream target genes in breast cancer cells. Novel second-generation rexinoids will reach phase I trials in years 4 and 5 of the project. A diverse team of scientists has been assembled with extensive expertise in retinoid research and clinical chemoprevention experience to move promising second-generation UAB rexinoids to phase I clinical trials.] This SPORE project impacts public health by the development of drugs that may prevent breast cancer.